Recommendations for Improving Methods and Models for Aquatic Hazard Assessment of Ionizable Organic Chemicals

Abstract

Ionizable organic chemicals (IOCs) such as organic acids and bases are an important substance class requiring aquatic hazard evaluation. Although the aquatic toxicity of IOCs is highly dependent on the water pH, many toxicity studies in the literature cannot be interpreted because pH was not reported or not kept constant during the experiment, calling for an adaptation and improvement of testing guidelines. The modulating influence of pH on toxicity is mainly caused by pHdependent uptake and bioaccumulation of IOCs, which can be described by ion-trapping and toxicokinetic models. The internal effect concentrations of IOCs were found to be independent of the external pH because of organisms' and cells' ability to maintain a stable internal pH milieu. If the external pH is close to the internal pH, existing quantitative structure-activity relationships (QSARs) for neutral organics can be adapted by substituting the octanol-water partition coefficient by the ionization-corrected liposome-water distribution ratio as the hydrophobicity descriptor, demonstrated by modification of the target lipid model. Charged, zwitterionic and neutral species of an IOC can all contribute to observed toxicity, either through concentration-additive mixture effects or by interaction of different species, as is the case for uncoupling of mitochondrial respiration. For specifically acting IOCs, we recommend a 2-step screening procedure with ion-trapping/QSAR models used to predict the baseline toxicity, followed by adjustment using the toxic ratio derived from in vitro systems. Receptor-or plasmabinding models also show promise for elucidating IOC toxicity. The present review is intended to help demystify the ecotoxicity of IOCs and provide recommendations for their hazard and risk assessment. Environ Toxicol Chem 2020;39:269-286. /ETC FIGURE 1: Speciation in relation to the pH and acid dissociation constant, pK a , for (A) monoprotic acids and (B) monoprotic bases. The experimentally accessible pH range is marked by blue (fish) and green (daphnia, algae) boxes. Further discussion on the experimentally accessible pH range is provided in the section Testing guidelines.

The Combined Algae Test for the Evaluation of Mixture Toxicity in Environmental Samples

“…When exposed to varying concentrations of diuron, both populations shifted to smaller cell sizes, which was less pronounced for Talaquil medium (Supplemental Data, Figure S9B) than for Altenburger medium (Supplemental Data, Figure S9C). The following experiments were performed with Talaquil medium because some of the chemicals tested are ionogenic, and the complex mixtures also typically need a higher buffer capacity (Escher et al 2020a).…”

Cytotoxicity Burst? Differentiating Specific from Nonspecific Effects in Tox21 in Vitro Reporter Gene Assays

“…2019 ). A potential ion-trapping effect does not need to be accounted for, provided the pH does not deviate much from pH 7.4, because ion-trapping becomes relevant only if the intracellular pH and the extracellular pH differ by more than one pH unit ( Escher et al. 2020 ).…”

“…The expansion of QSARs for neutral chemicals to ionizable chemicals was previously described for bacteria (Escher et al 2017) and the zebrafish embryo toxicity test (Klüver et al 2019). A potential ion-trapping effect does not need to be accounted for, provided the pH does not deviate much from pH 7.4, because ion-trapping becomes relevant only if the intracellular pH and the extracellular pH differ by more than one pH unit (Escher et al 2020).…”

“…The IC 10,baseline of all Tox21 chemicals were predicted with the baseline toxicity QSARs ( Table 1). The log K lip=w of the neutral species were predicted by a log K ow -based QSAR [ (Endo et al 2011), Equation 9] and the log D lip=w (pH 7.4) with Equation 10 that was derived from Equation 1 by assuming 10 times lower affinity of the ionized species to phospholipid liposomes (Bittermann et al 2016;Escher et al 2020). The fraction of the neutral and ionized species was calculated with the Henderson-Hasselbalch equation from the acidity constants pK a , which were estimated with ACD/Percepta pK a using the GALAS algorithm (www.acdlabs.com/software/pka/).…”

Assessing the Ecological Risks of Per‐ and Polyfluoroalkyl Substances: Current State‐of‐the Science and a Proposed Path Forward

“…given that anions have a higher affinity to proteins than their neutral counterparts (Escher et al 2020). Models that utilize molecular structure to predict behavior in organic and aqueous solvents are capable of estimating log K ow values for the neutral portion of PFAS (e.g., COSMOtherm; Wang 2011).…”